This research will be done in collaboration with Prof. Vladimir Markhasin primarily in Russia at Institute of Immunology and Physiology of Ural Brach of Russian Academy of Sciences, as an extension of NIH grant 5RO1HL5488704. Experimental and clinical data evidence that cardiac arrhythmias might result from coupling of mechanical inputs to electrical outputs through mechano-electric feedback (MEF). One of the key mechanisms underlying MEF at the cellular level is activation of mechanosensitive channels (MSCs) in heart tissue. The parent grant concerns specifically the general properties of MSCs, and their role in affecting action potentials (AP). Another mechanism providing mechanical effects on Ca 2+ handling is proved to be the mechano-dependent cooperative modulation of the affinity of troponin C for Ca 2+. We hypothesized that mechanically induced changes in Ca 2+ kinetics may alter the time course of the currents via Na+/Ca 2+ exchange, and thus affect AP duration. As far as we know, the interaction of MSC and Na+/Ca 2+ currents in normal or pathological conditions has not been studied either experimentally or theoretically. Within proposed FIRCA project we are going to test the effects of transport inhibitors, notably GsMTx-4 peptide (supplied by the PI) that block MSCs, and modulators of Ca 2+ handling (as Na+/Ca 2+ currents blockers), on the contractility, action potential configuration and intracellular Ca 2+ dynamics in one dimensional preparations of trabeculae and papillary muscles. To predict intracellular mechanisms of the experimental findings we will develop mathematical models of isopotential cells, and elucidate the role of the MSCs in and their comparative contribution to the origin of cardiac rhythm disturbances. It is well established in the whole heart that the distribution of mechanical strain during a systole plays a key role in the electromechanical function. This justifies our next goal to develop 1D and 2D mathematical models of myocardial tissue (virtual stands), and explore the influence of the deformation-induced stress/strain fields on electromechanical responses of virtual tissue and Ca 2+ kinetics. The Russian team has good expertise in studying mechanical activity of myocardium both experimentally on isolated muscle strips and theoretically by computer modeling. Their models successfully simulate the time course of muscle force and length together with Ca 2+ kinetics and electrical activity during contractions under different modes of muscle loading, and dynamical deformations. We will utilize Russian expertise for further model developing to study effects of contraction - excitation coupling in myocardium under simulated physiological conditions.